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Targeting glutaminase-mediated glutamine dependence in papillary thyroid cancer

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Abstract

Papillary thyroid cancer is a prevalent endocrine malignancy. Although alterations in glutamine metabolism have been reported in several types of hematological and solid tumors, little is known about the functions of glutamine and glutaminolysis-associated proteins in papillary thyroid cancer. Here, we demonstrated the glutamine dependence of papillary thyroid cancer cells, and with the use of RT2-PCR arrays, we screened for the aberrant overexpression of glutaminase in human papillary thyroid cancer tissues and cells. These results were later confirmed via real-time PCR, Western blots, and immunohistochemical staining. We found that the levels of glutaminase were significantly correlated with extrathyroidal extension. Inhibition of GLS suppressed glutaminolysis and reduced mitochondrial respiration. The proliferative, viable, migratory, and invasive abilities of papillary thyroid cancer cells were impaired by both the pharmacological inhibition and the genetic knockdown of glutaminase. Additionally, the inhibition of glutaminase deactivated the mechanistic target of the rapamycin complex 1 (mTORC1) signaling pathway, promoting autophagy and apoptosis. Collectively, these findings show that glutaminase-mediated glutamine dependence may be a potential therapeutic target for papillary thyroid cancer.

Key messages

  • PTC cells are glutamine-dependent, and GLS is aberrantly overexpressed in PTC.

  • Inhibition of GLS suppressed glutaminolysis and reduced mitochondrial respiration.

  • Inhibition of GLS impairs the viability of PTC cells.

  • GLS blockade causes deactivation of mTORC1 and induction of autophagy and apoptosis.

  • GLS may be a potential therapeutic target for PTC.

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Acknowledgments

We thank the technician Chao Guan for his generous help with preparing paraffin-embedded tissue blocks.

Funding

This work was supported by the Distinguished Young Scholars Growth Programs of Higher Education of Liaoning Province (grant number LJQ2015114), the Scientific Research Programs of Liaoning Educational Committee (grant number LK201625), the Natural Science Foundation of Liaoning Province (grant number 2014021039), the Endocrine Diseases Research Programs of Chinese Medical Association Clinical Medicine Scientific Research (grant number 13050810466), the Open Project Program of Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China (grant number KLTPM-SX2018-A2), and the Support Programs for Young Scientific and Technological Innovation Talents of Shenyang (grant number RC170058).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China

    Yang Yu, Xiaohui Yu, Chenling Fan, Hong Wang, Renee Wang & Haixia Guan

  2. Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, 110001, China

    Chen Feng

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  1. Yang Yu
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  2. Xiaohui Yu
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  3. Chenling Fan
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  4. Hong Wang
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  6. Chen Feng
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  7. Haixia Guan
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Correspondence to Chen Feng or Haixia Guan.

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The study was supported by the First Affiliated Hospital of China Medical University and was conducted in accordance with the Declaration of Helsinki. Tissue specimens were collected with patients’ informed consent according to institutional ethical guidelines approved by the Institute Research Ethics Committee.

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The authors declare that they have no conflict of interest.

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Yu, Y., Yu, X., Fan, C. et al. Targeting glutaminase-mediated glutamine dependence in papillary thyroid cancer. J Mol Med 96, 777–790 (2018). https://doi.org/10.1007/s00109-018-1659-0

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  • DOI: https://doi.org/10.1007/s00109-018-1659-0

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